Mild pain killer blocks action of key protein required for hearing

In continuation of my update on 'diflunisal'

A Rice University study has found that the aspirin-like drug diflunisal blocks the action of prestin, a key protein that is required for hearing.

The research, which is available online in the open-access journal PLOS ONE, stemmed from a 2015 Rice study that screened more than a half-dozen nonsteroidal anti-inflammatory drugs, or NSAIDs, for possible interactions with the protein prestin. Prestin is a highly specialized protein that drives the action of outer hair cells in the cochlea, an inner-ear organ that allows people and animals to hear.

"Taking too much aspirin can cause temporary deafness, and researchers discovered more than a decade ago that this happens because salicylate, one of the primary metabolites of aspirin, interferes with prestin," said study lead author Guillaume Duret, a research scientist in Rice's Department of Electrical and Computer Engineering. "Given the number of commonly used NSAIDs that operate in a similar way to aspirin, it seemed like a good idea to find out whether they also might inhibit prestin."

Duret said diflunisal was the only drug in the test that blocked the action of prestin. He said the findings suggest that the inhibition occurs by competing with chloride ions in prestin, a mechanism that is similar to what has been proposed for salicylate. The study also found that the dosage needed to induce a reaction was less than the aspirin dose required to induce a similar reaction.

Diflunisal is primarily prescribed as a mild pain killer and an anti-inflammatory for arthritis. But Duret said the findings come at an important time because the medical community is considering repurposing diflunisal as a possible treatment for both cancer and amyloid polyneuropathy.

"So far, it's been used in a pill form that is ingested, and the known side effects are for relatively small doses, like as if you were taking aspirin," Duret said. "For greater doses that are perhaps injected, the side effects may not yet be known."

He conducted the study's experiments in 2015 with two of the world's leading experts on prestin and outer hair cells, Rice bioengineer Rob Raphael and Baylor College of Medicine molecular biologist Fred Pereira.

Aspirin May Fight Cancer by Slowing DNA Damage

Researchers hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. Researchers  evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two researchers detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett's cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs. More...

Aspirin May Fight Cancer by Slowing DNA Damage | ucsf.edu

NSAIDs and Cardiovascular Risk Explained, According to Studies from the Perelman School of Medicine

NSAIDs and Cardiovascular Risk Explained, According to Studies from the Perelman School of Medicine: After nearly 13 years of study and intense debate, a pair of new papers from the Perelman School of Medicine, at the University of Pennsylvania have confirmed exactly how a once-popular class of anti-inflammatory drugs leads to cardiovascular risk for people taking...

Ref : http://www.uphs.upenn.edu/news/News_Releases/2012/05/risk/

Cobiprostone shows promise against NSAID-induced gastric mucosal injury

Cobiprostone shows promise against NSAID-induced gastric mucosal injury: Sucampo Pharmaceuticals, Inc. today announced the presentation of preclinical data at Digestive Disease Week 2012, in San Diego, which demonstrates the protective effect of cobiprostone (see structure)  against epithelial barrier dysfunction in models of non-steroidal anti-inflammatory drug (NSAID)-induced gastric mucosal injury.

Ref : http://investor.sucampo.com/phoenix.zhtml?c=201197&p=irol-newsArticle&ID=1697806&highlight=

Clinical study: Celecoxib drug may treat breast cancer

In continuation of m update on Celecoxib

Clinical study: Celecoxib drug may treat breast cancer

New anti-inflammatory drug shows promise for treating inflammatory disorders

In one of my earlier blog, I  did mention about the antiinflammatory activity of H₂S gas. Now interestingly John Wallace, a pharmacologist and director of the Farncombe Family Digestive Health Research Institute at McMaster University, compared naproxen, a commonly used NSAID, to a novel anti-inflammatory drug, ATB-346 (ATB-346 is a derivative of naproxen which releases hydrogen sulfide), which he developed in collaboration with a team of Italian chemists and is now commercializing through his company, Antibe Therapeutics Inc. The basis for this research is by the fact that hydrogen sulphide is an important mediator of gastric mucosal defence. As we all know the ulcerogenecity associated with NSAIDs, there is a need to have NSAIDs with least or no ulcerogenecity.

As per the claim by the researchers, ATB-346, [above, structure : 2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester] acts by inhibiting cyclooxygenase-1 and 2 and  reduces inflammation (in vivo). More interesting out come from their research is  that ATB-346 suppressed gastric prostaglandin E₂ synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. 

ATB-346 did not cause significant damage, where as naproxen rendered significant  gastric mucosa damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K_IR6.x channels). Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity, but with substantially reduced gastrointestinal toxicity (100 times safer than naproxen). Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats.

The researchers concluded that H2S-releasing NSAIDs appear to represent a promising alternative to existing therapies for the treatment of inflammation and pain. Future research will focus on the potential cardiovascular benefits of these drugs. .....

Ref : John L Wallace et. al., British Journal of Pharmacology, 159(6),  1236 - 1246

Naproxcinod a better NSAID.....

I knew  about Naproxen, because my first job was with Rallis India  Limited and the pharma division (sold to Shreya Group) was selling it as  a gel. It works by inhibiting both the COX-1 and COX-2 enzymes and that is the reason, why it has side effects. It has  been established already that the selective inhibitors of  COX-2 & 5 -LO will be the best drugs with least or no ulcerogenecity. We have  some drug like Celecoxib with selective inhibition of COX-2 (cyclo oxygenase enzyme), still we need to have selective inhibitors of both COX-2 & 5 -LO, so that  there will not be any cases like Rofecoxib withdrawal.

Naproxcinod, is a nitroxybutyl ester of naproxen. The ester group allow it to also act as a nitric oxide donor. Interestingly, this second mechanism of action makes naproxcinod the first of a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are expected to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.  Now NicOx S.A announced that European Medicines Agency (EMEA) has validated the Marketing Authorization Application (MAA) for naproxcinod. NicOx is seeking approval for an indication for the relief of the signs and symptoms of primary osteoarthritis. This follows the acceptance for filing of a New Drug Application (NDA) by the US Food and Drug Administration (FDA) in November 2009.

More interestingly, in addition to naproxcinod, NicOx's pipeline includes several nitric oxide- donating NCEs, which are in development internally and with partners, including Merck & Co., Inc., for the treatment of widespread eye diseases, cardiometabolic diseases, hypertension and dermatological disease.

Details of the press release, one can read at the link....

Vardenafil (PDE5 inhibitor) as antiulcer agent?

Vardenafil, (Levitra, Bayer) is a PDE5 inhibitor used for treating impotence (erectile dysfunction). Vardenafil's indications and contra-indications are the same as with other PDE5 inhibitors; it is closely related in function to sildenafil citrate (Viagra) and tadalafil (Cialis). Structurally, the difference between the vardenafil molecule and sildenafil citrate is a nitrogen atom's position and the change of sildenafil's piperazine ring methyl group to an ethyl group. Tadalafil is structurally different from both sildenafil and vardenafil. Vardenafil's relatively short effective time is comparable to but somewhat longer than sildenafil's.

We know that most of the NSAIDs are associated with ulcerogenecity. Though there are many compounds with different mode of action have been tested (and some of them are being used) to treat the peptic ulcer, compounds with phosphodiesterase 5 inhibitor were not tested before Dr. Karakaya of Zonguldak Karaelmas University-who have reported that Vardenafil can be used to treat the NSAID-induced gastric ulcer. As per the claim by the researchers the activity is dose dependent.

Ref : http://www.wjgnet.com/1007-9327/abstract_en.asp?f=5091&v=15